Syk
Encyclopedia
Spleen tyrosine kinase, also known as Syk, is an enyzme which in humans is encoded by the SYK gene.
, is a member of the Syk family of tyrosine kinase
s. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual SH2 domain
separated by a linker domain.
While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within B
and T cell
s respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor. Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, Fc Receptor
, and integrin
s.
and Tel
. Constitutive Syk activity can transform B cells. Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs
" (ITAMs) which lead to activation of Syk including Epstein Barr virus
, bovine leukemia virus
, and mouse mammary tumor virus
.
Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of autoimmune diseases. This has been demonstrated by the orally active inhibitor fostamatinib
(R788) in the treatment of rheumatoid arthritis
. The 6-month double-blind
, placebo
-controlled trial investigated clinical responses in 457 patients with rheumatoid arthritis
who were not sufficiently responsive to methotrexate
. The drug indeed caused a dose-dependent improvement in disease severity. The drug was however associated with an increase in the frequency in diarrhea, upper respiratory tract infections, neutropenia
. Moreover R788 increased blood pressure and a concomitant increase in treatment with antihypertensive drugs. The drug is investigational and at present the final position within the broad set of antirheumatic drugs and its long-term safety are unknown.
The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in Nasopharyngeal carcinoma
and head and neck cancer
while other authors have suggested a tumor suppressor role in breast
and gastric cancer.
with PTPN6
, LYN
, FCGR2A
, Lck
, Grb2
, VAV1
, FYN
, PTK2
, Cbl gene
and CRKL
.
Function
SYK, along with Zap-70ZAP-70
ZAP-70 is an abbreviation for Zeta-chain-associated protein kinase 70 . The protein is a member in the protein-tyrosine kinase family...
, is a member of the Syk family of tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
s. These non-receptor cytoplasmic tyrosine kinases share a characteristic dual SH2 domain
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
separated by a linker domain.
While Syk and Zap-70 are primarily expressed in hematopoietic tissues, there is expression of Syk in a variety of tissues. Within B
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
and T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s respectively, Syk and Zap-70 transmit signals from the B-Cell receptor and T-Cell receptor. Syk plays a similar role in transmitting signals from a variety of cell surface receptors including CD74, Fc Receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....
, and integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
s.
Clinical significance
Abnormal function of Syk has been implicated in several instances of hematopoeitic malignancies including translocations involving ItkITK (gene)
IL2-inducible T-cell kinase, also known as ITK, is a protein that in humans is encoded by the ITK gene.- Function :This gene encodes an intracellular tyrosine kinase expressed in T-cells...
and Tel
ETV6
ETV6 is an oncogene.-Interactions:ETV6 has been shown to interact with Grb2, FLI1 and HTATIP.-See also:* TEL-JAK2Mouse Mutant Alleles for Etv6 Marker Symbol for Mouse Gene. This symbol is assigned to the genomic locus by the...
. Constitutive Syk activity can transform B cells. Several transforming viruses contain "Immunoreceptor Tyrosine Activation Motifs
Immunoreceptor tyrosine-based activation motif
An immunoreceptor tyrosine-based activation motif is a conserved sequence of four amino acids that is repeated twice in the cytoplasmic tails of certain cell surface proteins of the immune system....
" (ITAMs) which lead to activation of Syk including Epstein Barr virus
Epstein-Barr virus
The Epstein–Barr virus , also called human herpesvirus 4 , is a virus of the herpes family and is one of the most common viruses in humans. It is best known as the cause of infectious mononucleosis...
, bovine leukemia virus
Bovine leukemia virus
Bovine leukemia virus is a bovine virus closely related to HTLV-I, a human tumour virus.BLV is a retrovirus which integrates a DNA intermediate as a provirus into the DNA of B-lymphocytes of blood and milk. It contains an oncogene coding for a protein called Tax. Nevertheless in its natural host...
, and mouse mammary tumor virus
Mouse mammary tumor virus
Mouse mammary tumor virus is a milk transmitted retrovirus like the HTL viruses, HI viruses and BLV. It belongs to the genus betaretroviruses. MMTV was formerly known as Bittner virus, and previously the 'milk factor' referring to the extra-chromosomal vertical transmission of murine breast cancer...
.
Given the central role of SYK in transmission of activating signals within B-cells, a suppression of this tyrosine kinase might aid in the treatment of autoimmune diseases. This has been demonstrated by the orally active inhibitor fostamatinib
Fostamatinib
Fostamatinib is an experimental drug candidate for the treatment of a variety of diseases. It is in Phase III clinical trials for rheumatoid arthritis and Phase II trials for autoimmune thrombocytopenia and...
(R788) in the treatment of rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
. The 6-month double-blind
Double-blind
A blind or blinded experiment is a scientific experiment where some of the people involved are prevented from knowing certain information that might lead to conscious or subconscious bias on their part, invalidating the results....
, placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
-controlled trial investigated clinical responses in 457 patients with rheumatoid arthritis
Rheumatoid arthritis
Rheumatoid arthritis is a chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. The process produces an inflammatory response of the synovium secondary to hyperplasia of synovial cells, excess synovial fluid, and the development...
who were not sufficiently responsive to methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...
. The drug indeed caused a dose-dependent improvement in disease severity. The drug was however associated with an increase in the frequency in diarrhea, upper respiratory tract infections, neutropenia
Neutropenia
Neutropenia, from Latin prefix neutro- and Greek suffix -πενία , is a granulocyte disorder characterized by an abnormally low number of neutrophils, the most important type of white blood cell...
. Moreover R788 increased blood pressure and a concomitant increase in treatment with antihypertensive drugs. The drug is investigational and at present the final position within the broad set of antirheumatic drugs and its long-term safety are unknown.
The role of Syk in epithelial malignancies is controversial. Several authors have suggested that abnormal Syk function facilitates transformation in Nasopharyngeal carcinoma
Nasopharyngeal carcinoma
Nasopharyngeal carcinoma is the most common cancer originating in the nasopharynx, the uppermost region of the pharynx , behind the nose where the nasal passages and auditory tubes join the remainder of the upper respiratory tract. NPC differs significantly from other cancers of the head and neck...
and head and neck cancer
Head and neck cancer
Head and neck cancer refers to a group of biologically similar cancers that start in the upper aerodigestive tract, including the lip, oral cavity , nasal cavity , paranasal sinuses, pharynx, and larynx. 90% of head and neck cancers are squamous cell carcinomas , originating from the mucosal lining...
while other authors have suggested a tumor suppressor role in breast
Breast cancer
Breast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
and gastric cancer.
Interactions
Syk has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PTPN6
PTPN6
Tyrosine-protein phosphatase non-receptor type 6 is an enzyme that in humans is encoded by the PTPN6 gene.Also known as Src homology region 2 domain-containing phosphatase-1 .-Interactions:...
, LYN
LYN
Tyrosine-protein kinase Lyn is a protein that in humans is encoded in humans by the LYN gene.Lyn is a member of the Src family of protein tyrosine kinases, which is mainly expressed in hematopoietic cells, in neural tissues liver, and adipose tissue. In various hematopoietic cells, Lyn has emerged...
, FCGR2A
FCGR2A
Low affinity immunoglobulin gamma Fc region receptor II-a is a protein that in humans is encoded by the FCGR2A gene.-Interactions:FCGR2A has been shown to interact with PIK3R1 and Syk.-Further reading:- External links :...
, Lck
Lck
Lck is a protein that is found inside specialized cells of the immune system called lymphocytes. Lck is a tyrosine kinase, which phosphorylates tyrosine residues of certain proteins involved in the intracellular signaling pathways of these lymphocytes...
, Grb2
Grb2
Growth factor receptor-bound protein 2 also known as Grb2 is an adaptor protein involved in signal transduction/cell communication. In humans, the GRB2 protein is encoded by the GRB2 gene....
, VAV1
VAV1
Proto-oncogene vav is a protein that in humans is encoded by the VAV1 gene.-Interactions:VAV1 has been shown to interact with Ku70, PLCG1, Lymphocyte cytosolic protein 2, Janus kinase 2, SIAH2, S100B, Abl gene, ARHGDIB, SHB, PIK3R1, PRKCQ, Grb2, MAPK1, Syk, Linker of activated T cells, Cbl gene and...
, FYN
FYN
Proto-oncogene tyrosine-protein kinase Fyn is an enzyme that in humans is encoded by the FYN gene.This gene is a member of the protein-tyrosine kinase oncogene family. It encodes a membrane-associated tyrosine kinase that has been implicated in the control of cell growth...
, PTK2
PTK2
PTK2 protein tyrosine kinase 2 , also known as Focal Adhesion Kinase , is a protein that, in humans, is encoded by the PTK2 gene. PTK2 is a focal adhesion-associated protein kinase involved in cellular adhesion and spreading processes...
, Cbl gene
Cbl gene
Cbl is a mammalian gene encoding several proteins including E3 ubiquitin-protein ligase CBL involved in cell signalling and protein ubiquitination...
and CRKL
CRKL
Crk-like protein is a protein that in humans is encoded by the CRKL gene.CrkL together with Crk participates in the Reelin signaling cascade downstream of DAB1.-Interactions:...
.